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Sequencing Therapy for Metastatic RCC: An Evidence-Based Analysis

Interview with Neeraj Agarwal

‘Filmed by PracticeUpdate with permission for inclusion on Uro Onco. More information and additional ASCO coverage can be found at www.practiceupdate.com

Interview transcript

Dr. Haffizulla: Thank you for joining us for this PracticeUpdate. I’m Dr. Farzanna Haffizulla. Joining me today is Dr. Neeraj Agarwal. Dr. Agarwal is an Associate Professor in the Department of Internal Medicine in the Division of Medical Oncology at the Huntsman Cancer Institute. We’re so happy to have you back here on PracticeUpdate.

Dr. Agarwal: Thanks for having me.

Dr. Haffizulla: So at this year’s ASCO, you are participating in educational sessions on sequencing therapies for metastatic renal cell carcinoma. Can you tell us first about your thought process for picking first-, second-, and third-line agents?

Dr. Agarwal: So this is…these are very exciting times for our patients because we have so many options available. These do create challenges for clinicians who have to pick one of these drugs for a given patient and there are no biomarkers available. So as you ask, first line, second line, third line, fourth line, how we choose a given agent for these lines, it presents a big challenge. So let’s start with the first line.  

Dr. Haffizulla: Okay.

Dr. Agarwal: First-line options are relatively limited and it makes it easier for the clinicians. So in our practice, if a patient is very healthy, has a good performance status, relatively younger, less than 65-year-old, we offer them treatment with high-dose interleukin-2 and these are approximately 10% to 15% patients who are offered high-dose interleukin-2, which is the only therapy associated with long-term durable responses lasting for years to decades. This therapy was approved first in 1992 and so far has remained the only therapy to be associated with durable long-term responses. But as you can see, there are only 10% to 15% patients who are going to be eligible for this kind of therapy. So other therapies are VEGF tyrosine kinase inhibitors. These are the ones which are usually called targeted therapies came into existence in the middle of last decade. Most commonly used drugs are sunitinib and pazopanib and in our practice we use sunitinib and pazopanib for the rest of the patients.

Dr. Haffizulla: Okay.

Dr. Agarwal: As you may recall, there is a drug, temsirolimus, which was approved based on its comparison with a non-standard-of-care drug known as interferon alpha in late last decade. But temsirolimus use has gone out of favor, mainly because a trial known as RECORD-3 trial showed superiority of sunitinib over mTOR inhibitor even in poor risk patients. So given that in first-line setting, barring patients with high-dose interleukin-2, my practice is to offer pretty much everybody else sunitinib or pazopanib.

Dr. Haffizulla: I see.

Dr. Agarwal: So, first-line treatment option is still pretty straightforward. Now coming to the salvage therapy setting, which is second line, third line, and fourth line, we had three new approvals in the last 1.5 years. There were two approvals from early part of this decade, everolimus and axitinib. Everolimus is an mTOR inhibitor and axitinib is a VEGF tyrosine kinase inhibitor. And these three new approvals, which came last year, within the last 1.5 years, all of them have been approved based on their comparison with single-agent everolimus.

And that’s why everolimus cannot be considered standard of care anymore because all these three new approvals were based on their comparison with everolimus where they showed superiority over everolimus.

In second-line setting now, we have four drugs, axitinib, cabozantinib, which is a VEGF tyrosine kinase inhibitor, which also targets AXL and c-MET and these are the novel targets, which are not targeted by any other VEGF TKIs in a clinically meaningful fashion yet.

The third combination is, or third agent is lenvatinib, which was tested in a clinical trial in combination with everolimus and compared to everolimus alone.

And the fourth one is an immunotherapy checkpoint inhibitor, nivolumab, which is a PD-1 checkpoint inhibitor.

So, now we have these four drugs for these patients who have progressed in first-line therapy setting. And how should I choose or what do I do to choose one of these drugs? So, I look at the patients.

When I have somebody who has received only immunotherapy in the first line, in my view, axitinib is the great choice for those patients because in the AXIS trial, which led to approval of axitinib, the patients who had immunotherapy only in the first-line setting, the median progression-free survival associated with axitinib was almost 12 months compared to the control sorafenib, which was only 6.5 months. So axitinib is unusually effective in patients who have only received or who had only received immunotherapy in the first line.

Dr. Haffizulla: Sure.

Dr. Agarwal: But as I told you just now, that only 10% to 15% patients are receiving immunotherapy in the first line. The majority of the patients are receiving sunitinib and pazopanib in the first line.

So we have three options left. Nivolumab, cabozantinib, and lenvatinib with everolimus. So, I look at the strength of evidence. So if you look at the trials, which led to approval of these agents, lenvatinib and everolimus was approved based on a phase 2 trial result with 100 patients, with the results from 100 patients.

On the other side, cabozantinib and nivolumab were approved based on randomized phase 3 trials with 600 to 900 patients.

So obviously, the level of evidence favoring cabozantinib and nivolumab is of much higher level than lenvatinib and everolimus. So I keep the second-line options confined to these two agents mostly, cabozantinib and nivolumab. And if I have to choose one of these, I basically look at the patients, are they willing to come to the hospital twice a month for intravenous infusion with nivolumab or they would rather like to see me once a month or maybe once in 6 weeks.

Dr. Haffizulla: I see.

Dr. Agarwal: So, a lot of patient preference and doctors’ own clinical experience is going to play a role in the decision making.

Dr. Haffizulla: So, biomarkers are not really part of the equation just yet in determining the sequence?

Dr. Agarwal: So, we don’t have prospectively validated biomarkers yet. In the absence of those biomarkers we cannot really use that.

Dr. Haffizulla: Sure. Of course. You need validated biomarkers as you mentioned. How far off are we from getting to that point would you estimate?

Dr. Agarwal: These are really encouraging results during ASCO this year, and based on that, I suspect we will have some really good biomarkers in the next 2 to 5 years. 

Dr. Haffizulla: So, I want to thank you very much for sharing your expertise and for all the excellent work that you’re doing here at ASCO and in all the clinical trial work.

Dr. Agarwal: Thank you, Farzanna.

Dr. Haffizulla: You’re very welcome. And to our viewers, thank you again for joining us for this PracticeUpdate. Please join us again soon. I’m Dr. Farzanna Haffizulla.